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Humans and Salamanders Share Abilities to Regenerate and Heal Print E-mail
SciMed - Biology
TS-Si News Service   
Thursday, 02 July 2009 21:00

Ambystoma mexicanum

Fairfax, VA, USA. Current research shows that both human and salamander tissues retain a kind of "memory" when they regenerate. With few exceptions, the new regenerated tissue is the same type as the original.

Salamander regeneration is legendary: the creatures are able to replace lost limbs, damaged lungs, sliced spinal cord — even bits of brain. It had been assumed that "pluripotent" cells, like human embryonic stem cells, were the source — they have the uncanny ability to morph into whatever appendage, organ or tissue happens to be needed or due for a replacement.

However, a team of scientists report in Nature that experiments on genetically modified axolotl salamanders show their direct similarity to humans. However, standard mammal stem cells operate with far less dramatic results — they can heal wounds or knit bone together, but not regenerate a limb or rebuild a spinal cord. The new findings are significant because they suggest that harnessing the salamander's regenerative process is within the realm of possibility for human medical science and replication in people.

Ambystoma mexicanum

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Axolotl salamanders, originally native to only one lake in central Mexico, are evolutionary oddities that become sexually reproducing adults while still in their larval stage. They are useful scientific models for studying regeneration because, unlike other salamanders, they can be bred in captivity and have large embryos that are easy to work on.

Also, the salamanders heal perfectly, without any scars whatsoever, another ability people would like to learn how to mimic, Maden said.

Malcolm Maden

Regarding the salamander, "I think it's more mammal-like than was ever expected," said Malcolm Maden, a professor of biology at the University of Florida (UF). "It gives you more hope for being able to someday regenerate individual tissues in people." Maden is a member of the UF Genetics Institute, and a contributing author to the paper.

When an axolotl loses, for example, a leg, a small bump forms over the injury called a blastema. It takes only about three weeks for this blastema to transform into a new, fully functioning replacement leg — not long considering the animals can live 12 or more years.

The cells within the blastema appear embryonic-like and originate from all tissues around the injury, including the cartilage, skin and muscle. As a result, scientists had long believed these cells were pluripotential — meaning they came from a variety of sites and could make a variety of things once functioning in their regenerative mode.

Maden and his colleagues at two German institutions tested that assumption using a tool from the transgenic kit: the GFP protein. When produced by genetically modified cells, GFP proteins have the useful quality of glowing livid green under ultraviolet light. This allows researchers to follow the origin, movement and destination of the genetically modified cells.

The researchers experimented on both adult and embryonic salamanders.

  • With the embryos, the scientists grafted transgenic tissue onto sites already known to develop into certain body parts, then observed how and where the cells organized themselves as the embryo developed.

    This approach allowed them to see, literally, what tissues the transgenic tissue made.

    In perhaps the most vivid result, the researchers grafted GFP-modified nerve cells onto the part of the embryo known to develop into the nervous system. Once the creatures developed, ultraviolet light exams of the adults revealed the GFP cells stretched only along nerve pathways — like glowing green strings throughout the body.

  • With the adults, they took tissue from specific parts or organs from transgenic GFP-producing axolotls, grafted it onto normal axolotls, then cut away a chunk of the grafted tissue to allow regeneration. They could then determine the fate of the grafted green cells in the emerging blastema and replacement tissue.

The researchers' main conclusions:

  • Only 'old' muscle cells make 'new' muscle cells, only old skin cells make new skin cells, only old nerve cells make new nerve cells, and so on.

  • The only hint that the axolotl cells could revamp their function came with skin and cartilage cells, which in some circumstances seemed to swap roles.

Maden said the findings will help researchers zero in on why salamander cells are capable of such remarkable regeneration. "If you can understand how they regenerate, then you ought to be able to understand why mammals don't regenerate," he said.

UF researchers will soon begin raising and experimenting on transgenic axolotls as part of the The Regeneration Project, an effort to treat human brain and other diseases by examining regeneration in salamanders, newts, starfish and flatworms.

CitationCells keep a memory of their tissue origin during axolotl limb regeneration. Martin Kragl, Dunja Knapp, Eugen Nacu, Shahryar Khattak, Malcolm Maden, Hans Henning Epperlein and Elly M. Tanaka. Nature 460(7251): 60-65. doi: 10.1038/nature08152

Abstract

During limb regeneration adult tissue is converted into a zone of undifferentiated progenitors called the blastema that reforms the diverse tissues of the limb. Previous experiments have led to wide acceptance that limb tissues dedifferentiate to form pluripotent cells. Here we have reexamined this question using an integrated GFP transgene to track the major limb tissues during limb regeneration in the salamander Ambystoma mexicanum (the axolotl). Surprisingly, we find that each tissue produces progenitor cells with restricted potential. Therefore, the blastema is a heterogeneous collection of restricted progenitor cells. On the basis of these findings, we further demonstrate that positional identity is a cell-type-specific property of blastema cells, in which cartilage-derived blastema cells harbour positional identity but Schwann-derived cells do not. Our results show that the complex phenomenon of limb regeneration can be achieved without complete dedifferentiation to a pluripotent state, a conclusion with important implications for regenerative medicine.

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Humans and Salamanders Share Abilities to Regenerate and Heal
Thursday, 02 July 2009

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